An Exciting Approval
- Enhertu (trastuzumab deruxtecan), a HER2-directed Antibody-Drug Conjugate, was approved for advanced non-small cell lung cancer (NSCLC) with HER2 mutations.
- Enhertu was evaluated at two dose levels. While response rates were consistent across dose levels, increased rates of ILD/pneumonitis were observed at the higher dose in patients with NSCLC.
- Eligibility for Enhertu requires patients to have unresectable or metastatic HER2-mutant NSCLC, with prior cancer treatments.
- “HER2 is mutated in only about 2% of patients with lung cancer, and this drug has been targeted to that small group, but data have emerged showing that it works in even a broader group of patients than were tested, and probably will benefit between 10% and 20% of patients with lung cancer,” Dr. Roy S. Herbst, Chief of Medical Oncology at Yale Cancer Center, told SurvivorNet.
Antibody-drug conjugates (ADCs) have emerged as a transformative therapeutic strategy in oncology, combining the precision of targeted therapy with the potency of cytotoxic drugs. Lung cancer, a leading cause of cancer-related deaths globally, has been a focus of recent advancements with ADCs, particularly for patients with specific genetic mutations such as HER2.
Understanding Antibody-Drug Conjugates
ADCs are complex molecules composed of three key components:
- Monoclonal Antibody: This component is engineered to target specific antigens present on cancer cells.
- Linker: A chemical linker connects the antibody to the cytotoxic drug. This linker is designed to remain stable in circulation but release the drug within the target cells.
- Cytotoxic Payload: The drug component, which is delivered directly into the cancer cells, induces cell death.
The rationale behind ADCs is to maximize the efficacy of chemotherapy while minimizing off-target effects, thereby improving the therapeutic index.
Approved by the FDA and European Commission, trastuzumab deruxtecan (brand name Enhertu) is the first HER2-directed ADC for patients with advanced non-small cell lung cancer (NSCLC) harboring HER2 mutations.
This approval was based on the impressive results from the DESTINY-Lung02 trial, which demonstrated substantial tumor shrinkage in patients who had progressed after previous therapies.
“This is an exciting development for our patients with a HER2 mutation as until this drug became available we did not have any standard HER2-targeted therapies available, and with the approval of this drug it is now established that biomarker testing for people with a new diagnosis of advanced lung adenocarcinoma should include testing for HER2 mutations,” Dr. Julia Rotow, Clinical Director of the Lowe Center for Thoracic Oncology, affiliated with Dana-Farber Cancer Institute, told SurvivorNet.
How Does Enhertu Work?
Enhertu is a HER2-directed antibody tethered to a chemotherapy drug. The antibody selectively binds to the HER2 proteins on the surface of breast cancer cells and infuses highly potent chemotherapy directly into those cancer cells. This selectivity allows for the sparing of normal cells and the consequent side effects.
“As Enhertu targets the protein HER2, attached to it is a toxin that hopefully will kill the cancerous cells. It’s targeting a therapy in a precise way by attaching to the tumor to deliver treatment,” Dr. Roy S. Herbst, Chief of Medical Oncology at Yale Cancer Center, told SurvivorNet.
Clinical Trial Data: DESTINY-Lung02
The DESTINY-Lung02 trial was pivotal in securing regulatory approvals for Enhertu. The study included patients with advanced or metastatic HER2-mutant NSCLC who had previously received systemic therapy. Enhertu was administered at two different doses (5.4 mg/kg and 6.4 mg/kg), with the lower dose being selected for approval due to a favorable balance of efficacy and safety.
Efficacy Outcomes
- Objective Response Rate (ORR): The trial reported an ORR of 49%, with one complete response and 49 partial responses among 102 patients.
- Duration of Response (DoR): The median DoR was 16.8 months, indicating the durability of the response in a significant proportion of patients
These results highlight the efficacy of Enhertu in a patient population with limited treatment options, offering a new therapeutic avenue for HER2-mutant NSCLC.
Who is Eligible for Enhertu?
To be eligible for treatment with Enhertu, patients must have unresectable or metastatic cancer, and they must have already received one or more cancer therapies.
NCCN Clinical Practice Guidelines recommends Enhertu as the only preferred 2L option for HER2-mutant mNSCLC.
“HER2 is mutated in only about 2% of patients with lung cancer, and this drug has been targeted to that small group, but data have emerged showing that it works in even a broader group of patients than were tested, and probably will benefit between 10% and 20% of patients with lung cancer, at least on the first go around,” adds Dr Herbst.
“Not all patients with lung cancer should receive this treatment, but it does mean that all potentially eligible patients should receive the correct tumor testing to know if their lung cancer has a HER2 mutation,” Dr. Rotow stressed.
“Specifically, everyone with advanced or metastatic lung adenocarcinoma should have this testing on their tumor biopsy sample, typically done through a type of testing called next generation sequencing,” Rotow added.
“Some patients with the other main subtype of non-small cell lung cancer, called squamous cell carcinoma, could also consider being tested. This is particularly important for younger patients and those without a history of tobacco use, for whom the chances are higher of finding a mutation like HER2 which may impact treatment options. HER2 is only one of multiple different gene alterations in lung cancer that have personalized therapies associated with them and an advantage of next-generation sequencing is that it includes all of these genes not just HER2.”
Dr. Herbst reinforces that only patients that have evidence of a HER2 abnormality should receive Enhertu, but he adds, “Research is ongoing, including here at Yale, to try to expand the impact to an even larger group. The DESTINY study is looking at this with broader groups of patients, with lower amounts of HER2 protein on their cell surface.”
Safety Profile
While ADCs offer targeted delivery of chemotherapy, they are not without risks. Enhertu, like other ADCs, is associated with both common and unique toxicities.
Grade 3 or higher drug-related adverse events occurred in 38.6% – 58.0% of patients, depending on the dose that were given.
The most frequent side effects include nausea, fatigue, and hematologic toxicities, similar to traditional chemotherapy. However, a notable concern with Enhertu is the risk of interstitial lung disease (ILD) or pneumonitis, which occurred in approximately 12% of patients in the clinical trials.
Early detection and management of ILD are crucial to mitigate this potentially life-threatening side effect.
